Abstract: Transcription is orchestrated by multiple types of regulatory proteins binding to DNA, but we do not yet understand how such binding events are integrated to give rise to specific gene expression patterns. Theoretical models of transcription can play a key role in deciphering how binding events are integrated by making our assumptions explicit and defining the limits of those assumptions. The dominant theoretical models for transcription rely on a number of simplifying assumptions that I will challenge. The first assumption is that regulatory DNA is modular (and thus can be considered independently of the rest of the genome). The second assumption is that transcription is controlled by a single rate limiting step (thus allowing it to be approximated by an equilibrium process). I will discuss how our recent theoretical and experimental work addresses these ideas directly, and strategies for developing quantitative frameworks that can accommodate critical features of eukaryotic gene regulation, such as locus topology, chromatin modification and remodeling.